Diabetes

1. Diabetes

2. Diabetes • Chronic disorder of carbohydrate, fat and protein metabolism due to defective or deficient insulin secretory response • Demographics: 3% of world population, 13 million in U.S. but only 50% are clinically diagnosed • 54,000 deaths/year in U.S., #7 leading cause of death • Lifetime risk: type 1 – 0.5%, type 2 – 5% • Numerous variations, all with hyperglycemia • Diagnosis: high fasting glucose or impaired glucose tolerance (without diabetes, oral glucose loads cause only slight rise in blood glucose due to brisk insulin response; with diabetes, blood glucose rises markedly for a sustained period) • Micro: Type 1 - inconsistent reduction in number and size of islets, uneven insulinitis (T lymphocytes) • Type 2 - subtle reduction in islet cell mass, amyloid replacement of islets due to amylin fibrils (also seen in • aging nondiabetics); associated with marked fatty replacement • Infants of diabetic mothers – islet cell hypertrophy/hyperplasia

3. Causes of Diabetes • Causes: destruction of islets due to • Pancreatitis • Tumours • Drugs (corticosteroids, thiazides, pentamidine) • Haemochromatosis (“bronze diabetes” due to hemosiderin deposition in pancreas) • Hereditary ceruloplasmin deficiency (copper deposition eg Wilson’s disease) • Surgery • Infections (congenital rubella, CMV, coxsackievirus) • Endocrinopathies (pituitary, adrenal, pregnancy) • Other: gestational diabetes or idiopathic

4. Long term complications • Damage to blood vessels in kidneys (nodular Kimmelstiel-Wilson glomerulopathy, pyelonephritis, papillary necrosis) • Eyes (exudative and proliferative retinopathy) • Nerves (symmetric polyneuropathy) • Peripheral vascular disease and coronary artery disease are major causes of morbidity / death

5. Type 1 Diabetes • Type 1A diabetes, Aka juvenile onset, IDDM; formerly called Type 1; 10% of all cases, is a chronic disorder that results from the immune-mediated destruction of the insulin-producing ß-cells of the pancreatic islets. • Onset at age < 20 years, normal weight, decreased blood insulin, anti-islet cell antibodies present, DKA common

6. Type 1 Diabetes • Autoimmunity: usually chronic (years); In its initial phase, which is clinically silent, T lymphocytes (CD8+ T cell infiltrate and other inflammatory cells) invade the islets and eventually destroy them. The disease then becomes clinically evident with the pathological consequences (hyperglycemia, ketosis and long-term complications) resulting from the inability to maintain glucose and lipid homeostasis. clinical disease when 90% of islet cells are destroyed • Islet cell autoantibodies seen in 70% of patients; antigens are glutamic acid decarboxylase (GAD), islet autoantigen 2, insulin associated antibody, gangliosides; GAD antibodies precede clinical symptoms • GAD antibody: in most newly diagnosed patients, 80% of first degree relatives; • GAD antibody causes stiff man syndrome, whose patients often have a history of Type I Diabetes

7. Stiff Man Syndrome • SMS is a rare, disabling neurological disorder characterised by progressive muscle rigidity and painful episodic spasms of the axial and proximal limb muscles.

8. Histology • Micro: Type 1 - inconsistent reduction in number and size of islets, uneven insulinitis (T-lymphocytes) • Infants of diabetic mothers – islet cell hypertrophy/hyperplasia

9. EarlyType 1 Diabetes

10. Type II Diabetes • Aka adult onset, NIDDM; formerly called type 2 • 80-90% of cases of diabetes • Usually > 30 years old, obese (80% of cases, abdominal obesity more important than subcutaneous obesity), • normal or increased blood insulin, no anti-islet antibodies, rare diabetic ketoacidosis • 90%+ concordance in twins, but no HLA association; apparently due to multiple genetic polymorphisms • Relative insulin deficiency is due to insulin resistance or derangement in beta cell secretion of insulin • Early: normal insulin secretion and plasma levels, but loss of pulsatile, oscillating pattern of secretion; also loss of rapid first phase of insulin secretion triggered by glucose; No insulinitis is present • Later: mild/moderate insulin deficiency, may be due to beta cell damage; beta cells may be “exhausted” due to chronic hyperglycemia and persistent beta cell stimulation • Insulin resistance in peripheral tissues also seen in obesity and pregnancy • Amylin: 37 amino acid peptide, normally produced by beta cells, packaged and cosecreted with insulin; in NIDDM patients, tends to accumulate outside beta cells and resembles amyloid • Note: Type II diabetes is associated with amyloid deposits in pituitary

11. Histology • Type 2 - subtle reduction in islet cell mass, amyloid replacement of islets due to amylin fibrils (also seen in aging nondiabetics); associated with marked fatty replacement

12. Type II Diabetes

13. Gestational Diabetes • Insulin resistance is a normal phenomenon emerging in the second trimester of pregnancy, which progresses thereafter to levels seen in non-pregnant patients with type 2 diabetes. It is thought to secure glucose supply to the growing foetus. • Women with GDM have an insulin resistance they cannot compensate with increased production in the β-cells of the pancreas. • The mechanism is unknown